Muranen, T.A., Greco, D., Blomqvist, C et al. (10 more authors) (2016) Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics in Medicine. ISSN 1098-3600
Abstract
Purpose CHEK2*1100delC is a founder variant in European populations conferring a 2-3 fold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods With genotype data of 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results The PRS conferred an odds ratio (OR) of 1.59 [95% CI 1.21-2.09] per standard deviation for BC for CHEK2*1100delC carriers and 1.58 [1.55-1.62] for non-carriers. No evidence for deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 [0.86-4.78] and for the lowest quintile 0.52 [0.16-1.74] for CHEK2*1100delC carriers, corresponding to over 34.0% and less than 15.0% life-time risk, respectively. Conclusion Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify the carriers at a high life-time risk for clinical actions.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Nature Publishing Group. This is an author produced version of a paper subsequently published in Genetics in Medicine. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Breast cancer; CHEK2*1100delC; Polygenic risk score (PRS); common variants; Breast Cancer Association Consortium (BCAC) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number YORKSHIRE CANCER RESEARCH S299 CANCER RESEARCH UK (CRUK) C5410/A7315. |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Oct 2016 14:48 |
Last Modified: | 14 Apr 2017 05:34 |
Published Version: | http://dx.doi.org/10.1038/gim.2016.147 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/gim.2016.147 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105685 |